American Association for Cancer Research
ccr-23-0011_supplementary_fig.3_suppsf3.pdf (242.39 kB)

Supplementary Fig. 3 from An Open-label Phase I Study of GDC-0927 in Postmenopausal Women with Locally Advanced or Metastatic Estrogen Receptor–Positive Breast Cancer

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posted on 2023-08-01, 08:41 authored by Sarat Chandarlapaty, Maura N. Dickler, Jose Alejandro Perez Fidalgo, Rafael Villanueva-Vázquez, Jennifer Giltnane, Mary Gates, Ching-Wei Chang, Sravanthi Cheeti, Jill Fredrickson, Xiaojing Wang, Ann Collier, Heather M. Moore, Ciara Metcalfe, Jennifer Lauchle, Eric W. Humke, Aditya Bardia

Supplementary Fig. S3. Clinical benefit does not correlate with ctDNA ESR1 mutant allele frequency (MAF) baseline levels or dynamics upon treatment, or with baseline ER and PR protein levels by IHC in tumor tissue.





GDC-0927 is a novel, potent, nonsteroidal, orally bioavailable, selective estrogen receptor (ER) degrader that induces tumor regression in ER+ breast cancer xenograft models. This phase I dose-escalation multicenter study enrolled postmenopausal women with ER+/HER2− metastatic breast cancer to determine the safety, pharmacokinetics, and recommended phase II dose of GDC-0927. Pharmacodynamics was assessed with [18F]-fluoroestradiol (FES) PET scans. Forty-two patients received GDC-0927 once daily. The MTD was not reached. The most common adverse events (AE) regardless of causality were nausea, constipation, diarrhea, arthralgia, fatigue, hot flush, back pain, and vomiting. There were no deaths, grade 4/5 AEs, or treatment-related serious AEs. Two patients experienced grade 2 AEs of special interest of deep vein thrombosis and jugular vein thrombosis, both considered unrelated to GDC-0927. Following dosing, approximately 1.6-fold accumulation was observed, consistent with the observed half-life and dosing frequency. There were no complete or partial responses. Pharmacodynamics was supported by >90% reduction in FES uptake and an approximately 40% reduction in ER expression, suggesting ER degradation is not the mechanistic driver of ER antagonism. Twelve patients (29%) achieved clinical benefit; 17 patients (41%) showed a confirmed best overall response of stable disease. Baseline levels of ER and progesterone receptor protein and mutant ESR1 circulating tumor DNA did not correlate with clinical benefit. GDC-0927 appeared to be well tolerated with pharmacokinetics supporting once-daily dosing. There was evidence of target engagement and preliminary evidence of antitumor activity in heavily pretreated patients with advanced/metastatic ER+/HER2− breast cancer with and without ESR1 mutations.

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